Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways.
Qichao Huang,Lei Zhan,Haiyan Cao,Jibin Li,Yinghua Lyu,Xu Guo,Jing Zhang,Lele Ji,Tingting Ren,Jiaze An,Bingrong Liu,Yongzhan Nie,Jinliang Xing +12 more
Reads0
Chats0
TLDR
It is demonstrated that increased mitochondrial fission plays a critical role in regulation of HCC cell survival, which provides a strong evidence for this process as drug target in HCC treatment.Abstract:
Mitochondrial morphology is dynamically remodeled by fusion and fission in cells, and dysregulation of this process is closely implicated in tumorigenesis. However, the mechanism by which mitochondrial dynamics influence cancer cell survival is considerably less clear, especially in hepatocellular carcinoma (HCC). In this study, we systematically investigated the alteration of mitochondrial dynamics and its functional role in the regulation of autophagy and HCC cell survival. Furthermore, the underlying molecular mechanisms and therapeutic application were explored in depth. Mitochondrial fission was frequently upregulated in HCC tissues mainly due to an elevated expression ratio of DNM1L to MFN1, which significantly contributed to poor prognosis of HCC patients. Increased mitochondrial fission by forced expression of DNM1L or knockdown of MFN1 promoted the survival of HCC cells both in vitro and in vivo mainly by facilitating autophagy and inhibiting mitochondria-dependent apoptosis. We further demonstrated that the survival-promoting role of increased mitochondrial fission was mediated via elevated ROS production and subsequent activation of AKT, which facilitated MDM2-mediated TP53 degradation, and NFKBIA- and IKK-mediated transcriptional activity of NFKB in HCC cells. Also, a crosstalk between TP53 and NFKB pathways was involved in the regulation of mitochondrial fission-mediated cell survival. Moreover, treatment with mitochondrial division inhibitor-1 significantly suppressed tumor growth in an in vivo xenograft nude mice model. Our findings demonstrate that increased mitochondrial fission plays a critical role in regulation of HCC cell survival, which provides a strong evidence for this process as drug target in HCC treatment.read more
Citations
More filters
Journal ArticleDOI
Tbx2 confers poor prognosis in glioblastoma and promotes temozolomide resistance with change of mitochondrial dynamics
TL;DR: The results indicated that Tbx2 might serve as an indicator for poor prognosis and also be useful as an important therapeutic in human GBM, which inhibits apoptosis through regulation of mitochondrial function.
Journal ArticleDOI
Probing the Mechanism of Hepatotoxicity of Hexabromocyclododecanes through Toxicological Network Analysis
TL;DR: A toxicological network analysis method is applied to predict the hepatotoxicity of three hexabromocyclodododecane diastereoisomers (α-HBCD, β-H BCD, and γ- HBCD) and explore their potential mechanisms, which is transferable to other toxicity research studies of environmental pollutants.
Journal ArticleDOI
Insights Into the Role of Mitochondria in Vascular Calcification
TL;DR: Current knowledge of mitochondrial dysfunction, dynamics anomalies, oxidative stress, and how it may relate to VC onset and progression is focused on and the main challenges and prerequisites for their therapeutic applications are discussed.
Journal ArticleDOI
Mfn2-mediated mitochondrial fusion promotes autophagy and suppresses ovarian cancer progression by reducing ROS through AMPK/mTOR/ERK signaling
Rahail Ashraf,Sanjay Kumar +1 more
Journal ArticleDOI
PDE2 Inhibits PKA-Mediated Phosphorylation of TFAM to Promote Mitochondrial Ca2+-Induced Colorectal Cancer Growth.
Yilin Zhao,Yaya Wang,Jing Zhao,Zhaohui Zhang,Mingpeng Jin,Feng Zhou,Feng Zhou,Chao Jin,Jing Zhang,Jinliang Xing,Nan Wang,Xianli He,Tingting Ren +12 more
TL;DR: In this article, the regulatory effects of mitochondrial Ca2+ on phosphodiesterase 2 (PDE2)/cAMP/PKA axis and the phosphorylation of mitochondrial transcription factor A (TFAM) as well as the growth of CRC cells were systematically investigated both in vitro and in vivo.
References
More filters
Journal ArticleDOI
Autophagy and the Integrated Stress Response
TL;DR: Autophagy is a cell biological process that is a central component of the integrated stress response and can be integrated with other cellular stress responses through parallel stimulation of autophagy and other stress responses by specific stress stimuli.
Journal ArticleDOI
Fission and selective fusion govern mitochondrial segregation and elimination by autophagy
Gilad Twig,Alvaro A. Elorza,Anthony J.A. Molina,Anthony J.A. Molina,Hibo Mohamed,Jakob D. Wikstrom,Gil Walzer,Linsey Stiles,Sarah E. Haigh,Steve Katz,Guy Las,Joseph Alroy,Min Wu,Bénédicte F. Py,Junying Yuan,Jude T. Deeney,Barbara E. Corkey,Orian S. Shirihai +17 more
TL;DR: Pulse chase and arrest of autophagy at the pre‐proteolysis stage reveal that fission followed by selective fusion segregates dysfunctional mitochondria and permits their removal by autophagic.
Journal ArticleDOI
Integrating cell-signalling pathways with NF-kappaB and IKK function.
TL;DR: This work has shown that crosstalk constitutes a decision-making process that determines the consequences of NF-κB and IKK activation and, ultimately, cell fate.
Journal ArticleDOI
Mitochondria: Dynamic Organelles in Disease, Aging, and Development
TL;DR: Recent work is discussed that suggests that the dynamics (fusion and fission) of these organelles is important in development and disease.
Journal ArticleDOI
Mitochondrial fusion and fission in cell life and death
TL;DR: The core components of the evolutionarily conserved fusion and fission machineries have now been identified, and mechanistic studies have revealed the first secrets of the complex processes that govern fusion andfission of a double membrane-bound organelle.